1. Field of the Invention
This invention relates to radiotberapeutic agents and peptides, radiodiagnostic agents and peptides, and methods for producing such labeled radiodiagnostic and radiotherapeutic agents. Specifically, the invention relates to calcitonin receptor binding peptides and derivatives and analogues thereof, and embodiments of such peptides labeled with gamma-radiation emitting isotopes such as technetium-99m (Tc-99m), as well as methods and kits for making, radiolabeling and using such peptides to image sites in a mammalian body. The invention also relates to calcitonin receptor binding peptides and derivatives and analogues thereof, labeled with cytotoxic radioisotopes such as rhenium-186 (.sup.186 Re) and rhenium-188 (.sup.188 Re), and methods and kits for making, radiolabeling and using such peptides therapeutically in a mammalian body.
2. Description of the Prior Art
Calcitonin (CT) is a peptide produced in the thyroid, the secretion of which results in inhibition of bone resorption and lowering of plasma calcium concentration (see Mone Zaidi et al., in Vitamins and Hormones v.46, 1991, Academic Press: New York, pp. 87-164). These effects are brought about via specific receptor-mediated processes in two major target organs: bone (in osteoclasts) and kidney. In bone, CT inhibits resorption (removal) of calcium by osteoclasts from plasma; in kidney, CT inhibits resorption of filtered divalent calcium ions (Ca.sup.2+) in the collecting ducts. Small amounts of CT have been administered to animals and humans without toxic effects. This result is due in part from the fact that the physiological effects of calcitonin are subtle even at maximum receptor occupancy and occur over a long time course. The major localization sites for administered CT are kidney, liver and the epiphyses of the long bones. Intravenously-administered calcitonin clears the blood rapidly and is excreted primarily in urine.
Human CT (hCT) is a 32 amino acid peptide containing a disulfide-cyclized heptapeptide amino terminus. CT from two other species (salmon and eel) are 50% homologous to the hCT amino acid sequence, but have a 10-fold higher affinity to CT receptor (CTR; IC.sub.50 =0.78 nM; Findlay et al., ibid.). These peptides have the following amino acid sequences:
hCT CGNLSTCMLG.TYTQD.FNKFH.TFPQT.AIGVG.AP.amide (SEQ ID NO. 1) PA1 sCT CSNLSTCVLG.KLSQE.LHKLQ.TYPRT.NTGSG.TP.amide (SEQ ID NO. 2) PA1 eCT CSNLSTCVLG.KLSQE.LHKLQ.TYPRT.DVGAG.TP.amide (SEQ ID NO. 3) PA1 IIa. -(amino acid).sup.1 -(amino acid).sup.2 -A-CZ(B)-{C(R.sup.1 R.sup.2)}.sup.n -X}, PA1 IIb. -A-CZ(B)-{C(R.sup.1 R.sup.2)}.sup.n -X}-(amino acid).sup.1 -(amino acid).sup.2, PA1 IIc. -(a primary .alpha.,.omega.- or .beta.,.omega.-diamino acid)-(amino acid).sup.1 -A-CZ(B)-{C(R.sup.1 R.sup.2)}.sup.n -X}, or PA1 IId. -A-CZ(B)-{C(R.sup.1 R.sup.2)}.sup.n -X}(amino acid).sup.1 -(a primary .alpha.,.beta.- or .beta.,.gamma.-diamino acid) PA1 diethylenetriaminepentaacetic acid (DTPA) PA1 (HOOCCH.sub.2).sub.2 N(CR.sub.2)(CR.sub.2)N(CH.sub.2 COOH)(CR.sub.2)(CR.sub.2)N(CH.sub.2 COOH).sub.2 PA1 ethylenediaminetetraacetic acid (EDTA) PA1 (HOOCCH.sub.2).sub.2 N(CR.sub.2)(CR.sub.2)N(CH.sub.2 COOH).sub.2 PA1 1,4,7,10-tetraazadodecanetetraacetic acid ##STR3## where n is an integer that is 2 or 3 and where each R is independently H, C.sub.1 to C.sub.4 alkyl, or aryl and one R is covalently linked to calcitonin receptor binding compound, or desferrioxamine. PA1 (i) a group having the formula: ##STR4## (ii) a group having the formula: ##STR5## wherein n, m and p are each integers that are independently 0 or 1; each R' is independently H, lower alkyl, C.sub.2 -C.sub.4 hydroxyalkyl, or C.sub.2 -C.sub.4 alkoxyalkyl, and each R is independently H or R", where R" is substituted or unsubstituted lower alkyl or phenyl not comprising a thiol group, and one R or R' is L, where L is a bivalent linker moiety linking the metal chelator to the targeting moiety and wherein when one R' is L, NR'.sub.2 is an amine. PA1 (amino acid).sup.1 -(amino acid).sup.2 -cysteine-, PA1 (amino acid).sup.1 -(amino acid).sup.2 -isocysteine-, PA1 (amino acid).sup.1 -(amino acid).sup.2 -homocysteine-, PA1 (amino acid).sup.1 -(amino acid).sup.2 -penicillamine-, PA1 (amino acid).sup.1 -(amino acid).sup.2 -2-mercaptoethylamine-, PA1 (amino acid).sup.1 -(amino acid).sup.2 -2-mercaptopropylamine-, PA1 (amino acid).sup.1 -(amino acid).sup.2 -2-mercapto-2-methylpropylamine-, PA1 (amino acid).sup.1 -(amino acid).sup.2 -3-mercaptopropylamine-, PA1 --cysteine-(amino acid)-(.alpha.,.beta.- or .beta.,.gamma.-diamino acid); PA1 --isocysteine-(amino acid)-(.alpha.,.beta.- or .beta.,.gamma.-diamino acid); PA1 --homocysteine-(amino acid)-(.alpha.,.beta.- or .beta.,.gamma.-diamino acid); PA1 --penicillamine-(amino acid)-(.alpha.,.beta.- or .beta.,.gamma.-diamino acid); PA1 2-mercaptoacetic acid-(amino acid)-(.alpha.,.beta.- or .beta.,.gamma.-diamino acid); PA1 2- or 3-mercaptopropionic acid-(amino acid)-(.alpha.,.beta.- or .beta.,.gamma.-diamino acid); PA1 2-mercapto-2-methylpropionic acid-(amino acid)-(.alpha.,.beta.- or .beta.,.gamma.-diamino acid); PA1 --CH.sub.2 -aryl (aryl is phenyl or alkyl or alkyloxy substituted phenyl); PA1 --CH-(aryl).sub.2, (aryl is phenyl or alkyl or alkyloxy substituted phenyl); PA1 --C-(aryl).sub.3, (aryl is phenyl or alkyl or alkyloxy substituted phenyl); PA1 --CH.sub.2 -(4-methoxyphenyl); PA1 --CH-(4-pyridyl)(phenyl).sub.2 ; PA1 --C(CH.sub.3).sub.3 --9-phenylfluorenyl; PA1 --CH.sub.2 NHCOR (R is unsubstituted or substituted alkyl or aryl); PA1 --CH.sub.2 -NHCOOR (R is unsubstituted or substituted alkyl or aryl); PA1 --CONHR (R is unsubstituted or substituted alkyl or aryl); PA1 --CH.sub.2 --S--CH.sub.2 -phenyl PA1 CH.sub.2 CO.SNLST.Hhc.VLGKLSCELHKLQTYPRTNTGSGTP.amide (SEQ ID No. 5), PA1 CH.sub.2 CO.SNLST.Hcy.VLGKLSCELHKLQTYPRTNTGSGTP.amide (SEQ ID No. 6), PA1 CH.sub.2 CO.SNLST.Cys.VLGKLSCELHKLQTYPRTNTGSGTP.amide (SEQ ID No. 7), and PA1 SNLST.Asu.VLGKLSCELHKLQTYPRTNTGSGTP.amide (SEQ ID No. 8). PA1 CH.sub.2 CO.SNLST.Hhc.VLGKLSC(BAT)ELHKLQTYPRTNTGSGTP.amide (SEQ ID No. 4), PA1 CH.sub.2 CO.SNLST.Hhc.VLGKLSQELHKLQTYPRTNTGSGTP(.epsilon.-K)GC.amide, PA1 CH.sub.2 CO.SNLST.Hhc.VLGKLSC(CH.sub.2 CO.GGCK.amide)ELHKLQTYPRTNTGSGTP.amide, PA1 CH.sub.2 CO.SNLST.Hhc.VLGKLSC(CH.sub.2 CO.(.beta.-Dap)KCK.amide)ELHKLQTYPRTNTGSGTP.amide, PA1 CH.sub.2 CO.SNLST.Hhc.VLGKLSC(CH.sub.2 CO.(.epsilon.-K)GCE.amide)ELHKLQTYPRTNTGSGTP.amide, PA1 CH.sub.2 CO.SNLST.Hcy.VLGKLSC(CH.sub.2 CO.GGCK.amide)ELHKLQTYPRTNTGSGT.amide, PA1 CH.sub.2 CO.SNLST.Hcy.VLGKLSC(CH.sub.2 CO.(.beta.-Dap)KCK.amide)ELHKLQTYPRTNTGSGTP.amide, PA1 CH.sub.2 CO.SNLST.Hcy.VLGKLSC(CH.sub.2 CO.(.epsilon.-K)GCE.amide)ELHKLQTYPRTNTGSGTP.amide, PA1 CH.sub.2 CO.SNLST.Cys.VLGKLSC(CH.sub.2 CO.GGCK.amide)ELHKLQTYPRTNTGSGTP.amide, PA1 CH.sub.2 CO.SNLST.Cys.VLGKLSC(CH.sub.2 CO.(.beta.-Dap)KCK.amide)ELHKLQTYPRTNTGSGTP.amide, PA1 CH.sub.2 CO.SNLST.Cys.VLGKLSC(CH.sub.2 CO.(.epsilon.-K)GCE.amide)ELHKLQTYPRTNTGSGTP.amide, PA1 SNLST.Asu.VLGKLSC(CH.sub.2 CO.(.beta.-Dap)KCK.amide)ELHKLQTYPRTNTGSGTP.amide, and PA1 SNLST.Asu.VLGKLSC(CH.sub.2 CO.(.beta.-Dap)KCK.amide)ELHKLQTYPRTDVGAGTP.amide.
(where single-letter abbreviations for amino acids can be found in Zubay, Biochemistry 2d ed., 1988, MacMillan Publishing: New York, p. 33, and where the underlined amino acids between the two cysteine residues in the amino terminal portion of the peptide represent a disulfide bond).
It has been shown that (ASu.sup.1,7)eCT (wherein the amino terminal cysteine residue is removed, the cysteine residue at position 7 has been substituted with 2-amino suberic acid and the cyclic disulfide has been replaced with a cyclic amide formed between the amino terminus and the side chain carboxylic acid moiety of the 2-amino suberic acid residue) binds to CT receptor with equal affinity as eCT itself and is much more resistant to proteolytic degradation at the receptor than the native peptide (Morikawa et al., 1976, Experientia 32: 1104-1106). There is also some evidence that truncated calcitonin peptide derivatives (such as Cbz-LHKLQY-OMe) retain substantial receptor binding activity (see Epand et al., 1988, J. Med. Chem. 31: 1595-1598).
CT peptides are readily synthesized using automated solid phase peptide synthesis, with the chemically-labile disulfide replaced with a stable congener. Position 14 of the peptide can be substituted without substantial loss of biological activity. (Moseley et al., 1982, J. Biol. Chem. 257: 5846-5851).
There is a need in the art for diagnostic agents that allow the detection and localization of tumors in a mammalian, particularly human, body. Current imaging modalities, such as computer-assisted tomography and magnetic resonance imaging can detect a lesion but cannot provide any information of whether a lesion is malignant, for example. Metastatic disease in particular is often difficult to detect using conventional imaging modalities. There is a need for diagnostic imaging agents that allow characterization of such lesions in vivo, preferably non-invasively, and particularly with regard to the detection of metastatic disease. Recently, it has been reported that cell surface receptors for CT are overexpressed in certain breast, lung, ovarian and lymphoma cancer cell lines (Findlay et al., 1981, Biochem. J. 196: 513-520). The present inventors have determined that the presence of calcitonin receptors on the cell surface of tumor cells (in lung and ovarian adenocarcinoma, breast cancers and lymphomas,for example) can be exploited as a marker to locate and identify such tumor cells in vivo, by providing detectably-labeled calcitonin receptor-binding peptides as described herein.
A variety of radionuclides are known to be useful for radioimaging, including .sup.67 Ga, .sup.99m Tc (Tc-99m), .sup.111 In and .sup.123 I. A number of factors must be considered for optimal radioimaging in humans. To maximize the efficiency of detection, a radionuclide that emits gamma energy in the 200 to 200 keV range is preferred. To minimize the absorbed radiation dose to the patient, the physical half-life of the radionuclide must be as short as the imaging procedure will allow. To allow for examinations to be performed on any day and at any time of the day, it is advantageous to have a source of the radionuclide always available at the clinical site.
Radioiodination of calcitonin peptides has been shown in the prior art.
Hunt et al., 1977, Br. J. Cancer 35: 401-406 describe radioiodination of calcitonin.
Findlay et al., 1981, Biochem. J. 196: 513-520 described use of radioiodinated calcitonin to demonstrate calcitonin receptor binding in human breast cancer cell lines.
Tc-99m is a preferred radionuclide because it emits gamma radiation at 140 keV, it has a physical half-life of 6 hours, and it is readily available on-site using a molybdenum-99/technetium-99m generator. Other radionuclides used in the prior art for radioimaging are less advantageous than Tc-99m. This is because the physical half-life of some such radionuclides is longer, resulting in a greater amount of absorbed radiation dose to the patient (e.g., indium-111). Alternatively, the gamma radiation energies of such alternate radionuclides are significantly lower (e.g., iodine-125) or higher (e.g., iodine-131) than Tc-99m and are thereby inappropriate for quality scintigraphic imaging. Lastly, many disadvantageous radionuclides cannot be produced using an on-site generator.
Tc-99m is a transition metal that is advantageously chelated by a metal complexing moiety. Radiolabel complexing moieties capable of binding Tc-99m can be covalently linked to various specific binding compounds to provide a means for radiolabeling such specific binding compounds. This is because the most commonly available chemical species of Tc-99m, pertechnetate (TcO.sub.4.sup.-), cannot bind directly to most specific binding compounds strongly enough to be useful as a radiopharmaceutical. Complexing of Tc-99m with radiolabel complexing moieties typically entails chemical reduction of the pertechnetate using a reducing agent such as stannous chloride.
Although Tc-99m is the preferred radionuclide for scintigraphic imaging, it has not been widely used for labeling peptides (see Lamberts, 1991, J. Nucl. Med. 32: 1189-1191). This is because methods known in the prior art for labeling larger protein molecules (i.e., &gt;10,000 daltons in size) with Tc-99m are not suitable for labeling peptides and other small molecules having a molecular size less than 10,000 daltons. Consequently, it is necessary to radiolabel most peptides by covalently attaching a radionuclide chelating moiety to the peptide, and so that the chelator is incorporated site-selectively at a position in the peptide that will not interfere with the specific binding properties of the peptide.
Methods for labeling peptides with Tc-99m are disclosed in co-owned U.S. Pat. Nos. 5,225,180, 5,405,597, 5,443,815, 5,508,020, 5,561,220, 5,620,675, and in co-pending U.S. patent applications Ser. Nos. 07/653,012, now abandoned, which issued as U.S. Pat. No. 5,811,394; 07/851,074, now abandoned, a divisional of which issued as U.S. Pat. No. 5,711,931; 07/871,282, a divisional of which issued as U.S. Pat. No. 5,780,007; 07/886,752, now abandoned which issued as U.S. Pat. No. 5,849,260; 07/902,935, which issued as U.S. Pat. No. 5,716,596; 07/955,466, now abandoned; 08/019,864, which issued as U.S. Pat. No. 5,552,525; 08/044,825 now abandoned, which issued as U.S. Pat. No. 5,645,815; 08/095,760, which issued as U.S. Pat. No. 5,620,675; 08/210,822, now abandoned; and PCT International Applications PCT/US92/00757, PCT/US92/10716, PCT/US93/02320, PCT/US93/03687, PCT/US93/04794, PCT/US93/05372, PCT/US93/06029, PCT/US93/09387, and PCT/US94/01894, which are hereby incorporated by reference.
Methods for preparing Tc-99m complexes are known in the art.
Byrne et al., U.S. Pat. Nos. 4,434,151, 4,575,556 and 4,571,430 describe homocysteine thiolactone-derived bifunctional chelating agents.
Fritzberg, U.S. Pat. No. 4,444,690 describes a series of technetium-chelating agents based on 2,3-bis(mercaptoacetamido) propanoate.
Nosco et al., U.S. Pat. No. 4,925,650 describe Tc-99m chelating complexes.
Kondo et al., European Patent Application, Publication No. 483704 A1 disclose a process for preparing a Tc-99m complex with a mercapto-Gly-Gly-Gly moiety.
European Patent Application No. 84109831.2 describes bisamido, bisthiol Tc-99m ligands and salts thereof as renal finction monitoring agents.
Davison et al., 1981, Inorg. Chem. 20: 1629-1632 disclose oxotechnetium chelate complexes.
Fritzberg et al., 1982, J. Nucl. Med. 23: 592-598 disclose a Tc-99m chelating agent based on N, N'-bis(mercaptoacetyl)-2,3-diaminopropanoate.
Byrne et al., 1983, J. Nucl. Med. 24: P126 describe homocysteine-containing Tc-99m chelating agents.
Bryson et al., 1988, Inorg. Chem. 27: 2154-2161 describe neutral complexes of technetium-99 which are unstable to excess ligand.
Misra et al., 1989, Tet. Lett. 30: 1885-1888 describe bisamine bisthiol compounds for radiolabeling purposes.
The use of chelating agents for radiolabeling protein and other specific-binding compounds is known in the art.
Gansow et al., U.S. Pat. No. 4,472,509 teach methods of manufacturing and purifying Tc-99m chelate-conjugated monoclonal antibodies.
Stavrianopoulos, U.S. Pat. No. 4,943,523 teach detectable molecules comprising metal chelating moieties.
Fritzberg et al., European Patent Application No. 86100360.6 describe dithiol, diamino, or diamidocarboxylic acid or amine complexes useful for making technetiumlabeled imaging agents.
Albert et al., UK Patent Application 8927255.3 disclose radioimaging using somatostatin derivatives such as octreotide labeled with .sup.111 In via a chelating group bound to the amino-terminus.
Albert et al., European Patent Application No. WO 91/01144 disclose radioimaging using radiolabeled peptides related to growth factors, hormones, interferons and cytokines and comprised of a specific recognition peptide covalently linked to a radionuclide chelating group.
Fischman et al., International Patent Application, Publication No. W093/13317 disclose chemotactic peptides attached to chelating moieties.
Kwekkeboom et al., 1991, J. Nucl. Med. 32: 981 Abstract #305 relates to radiolabeling somatostatin analogues with .sup.111 In.
Albert et al., 1991, Abstract LM10, 12th American Peptide Symposium: 1991 describe uses for .sup.111 In-labeled diethylene-triaminopentaacetic acid-derivatized somatostatin analogues.
Cox et al., 1991, Abstract, 7th International Symposium on Radiopharmacology, p. 16, disclose the use of, Tc-99m-, .sup.131 I- and .sup.111 In-labeled somatostatin analogues in radiolocalization of endocrine tumors in vivo by scintigraphy.
Methods for labeling certain specific-binding compounds such as antibodies with Tc-99m are known in the prior art.
Hnatowich, U.S. Pat. No. 4,668,503 describe Tc-99m protein radiolabeling.
Tolman, U.S. Pat. No. 4,732,684 describe conjugation of targeting molecules and fragments of metallothionein.
Nicolotti et al., U.S. Pat. No. 4,861,869 describe bifunctional coupling agents useful in forming conjugates with biological molecules such as antibodies.
Fritzberg et al., U.S. Pat. No. 4,965,392 describe various S-protected mercaptoacetylglycylglycine-based chelators for labeling proteins.
Schochat et al., U.S. Pat. No. 5,061,641 disclose direct radiolabeling of proteins comprised of at least one "pendent" sulfhydryl group.
Fritzberg et al., U.S. Pat. No. 5,091,514 describe various S-protected mercaptoacetylglycylglycine-based chelators for labeling proteins.
Gustavson et al., U.S. Pat. No. 5,112,953 disclose Tc-99m chelating agents for radiolabeling proteins.
Kasina et al., U.S. Pat. No. 5,175,257 describe various combinations of targeting molecules and Tc-99m chelating groups.
Dean et al., U.S. Pat. No. 5,180,816 disclose methods for radiolabeling a protein with Tc-99m via a bifunctional chelating agent.
Sundrehagen, International Patent Application, Publication No. WO85/03231 disclose Tc-99m labeling of proteins.
Reno and Bottino, European Patent Application 87300426.1 disclose radiolabeling antibodies with Tc-99m.
Bremer et al., European Patent Application No. 87118142.6 disclose Tc-99m radiolabeling of antibody molecules.
Pak et al., European Patent Application No. WO 88/07382 disclose a method for labeling antibodies with Tc-99m.
Goedemans et al., PCT Application No. WO 89/07456 describe radiolabeling proteins using cyclic thiol compounds, particularly 2-iminothiolane and derivatives.
Dean et al., International Patent Application, Publication No. WO89/12625 teach bifunctional coupling agents for Tc-99m labeling of proteins.
Schoemaker et al., International Patent Application, Publication No. WO90/06323 disclose chimeric proteins comprising a metal-binding region.
Thornback et al., EPC Application No. 90402206.8 describe preparation and use of radiolabeled proteins using thiol-containing compounds, particularly 2-iminothiolane.
Gustavson et al., International Patent Application, Publication No. WO91/09876 disclose Tc-99m chelating agents for radiolabeling proteins.
Rhodes, 1974, Sem. Nucl. Med. 4: 281-293 teach the labeling of human serum albumin with technetium-99m.
Khaw et al., 1982, J. Nucl. Med. 23: 1011-1019 disclose methods for labeling biologically active macromolecules with Tc-99m.
Schwartz et al., 1991, Bioconjugate Chem. 2: 333 describe a method for labeling proteins with Tc-99m using a hydrazinonicotinamide group.
Attempts at labeling peptides have been reported in the prior art.
Ege et al., U.S. Pat. No. 4,832,940 teach radiolabeled peptides for imaging localized T-lymphocytes.
Morgan et al., U.S. Pat. No. 4,986,979 disclose methods for imaging sites of inflammation.
Flanagan et al., U.S. Pat. No. 5,248,764 describe conjugates between a radiolabel chelating moiety and atrial natiuretic factor-derived peptides.
Ranby et al., 1988, PCT/US88/02276 disclose a method for detecting fibrin deposits in an animal comprising covalently binding a radiolabeled compound to fibrin.
Lees et al., 1989, PCT/US89/01854 teach radiolabeled peptides for arterial imaging.
Morgan et al., International Patent Application, Publication No. WO90/10463 disclose methods for imaging sites of inflammation.
Flanagan et al., European Patent Application No. 90306428.5 disclose Tc-99m labeling of synthetic peptide fragments via a set of organic chelating molecules.
Stuttle, PCT Application, Publication No. WO 90/15818 suggests Tc-99m labeling of RGD-containing oligopeptides.
Rodwell et al., 1991, PCT/US91/03116 disclose conjugates of "molecular recognition units" with "effector domains".
Cox, International Patent Application No. PCT/US92/04559 discloses radiolabeled somatostatin derivatives containing two cysteine residues.
Rhodes et al., International Patent Application, Publication No. WO93/12819 teach peptides comprising metal ion-binding domains.
Lyle et al, International Patent Application, Publication No. WO93/15770 disclose Tc-99m chelators and peptides labeled with Tc-99m.
Coughlin et al, International Patent Application, Publication No. WO93/21151 disclose bifunctional chelating agents comprising thiourea groups for radiolabeling targeting molecules.
Knight et al., 1990, 37th Annual Meeting of the Society of Nuclear Medicine, Abstract #209, claim thrombus imaging using Tc-99m labeled peptides.
Babich et al., 1993, J. Nucl. Med. 34: 1964-1974 describe Tc-99m labeled peptides comprising hydrazinonicotinamide derivatives.
The present inventors have developed Tc-99m labeled, small, synthetic, calcitonin-derived peptides possessing both the capacity for high-affinity binding to calcitonin receptors and favorable pharmacokinetics to permit efficient in vivo localization at tumor sites in this art to provide more specific imaging of important tumor cell types. Such labeled peptides provide rapid, cost-effective, non-invasive diagnostic imaging procedures useful for initial disease staging and evaluation of metastatic spread of the disease. Such peptides also provide ways to assess the therapeutic effectiveness by non-invasive localization of CTR-expressing tumor cells following surgery, radiation therapy or chemotherapy.
Calcitonin receptor binding peptides and radiolabeled derivatives and analogues thereof can also be used therapeutically. For these applications, cytotoxic radioisotopes are advantageous, such as rhenium-186 and rhenium-188.
There remains a need for synthetic (to make routine manufacture practicable and to ease regulatory acceptance) calcitonin receptor binding compounds, including peptides, derivatives and analogues thereof to be used as scintigraphic agents particularly when radiolabeled with Tc-99m for use in imaging tumors in vivo, and as radiotherapeutic agents when radiolabeled with a cytotoxic radioisotope such as rhenium-186 and rhenium-188. Small synthetic calcitonin receptor binding peptides and derivatives and analogues of such calcitonin receptor binding peptides that specifically fulfill this need are provided by this invention.